Genetic Ablation of AXL Does Not Protect Human Neural Progenitor Cells and Cerebral Organoids From Zika Virus Infection

Cell Stem Cell. 2016 Dec 1;19(6):703-708. doi: 10.1016/j.stem.2016.11.011.

Abstract

Zika virus (ZIKV) can cross the placental barrier, resulting in infection of the fetal brain and neurological defects including microcephaly. The cellular tropism of ZIKV and the identity of attachment factors used by the virus to gain access to key cell types involved in pathogenesis are under intense investigation. Initial studies suggested that ZIKV preferentially targets neural progenitor cells (NPCs), providing an explanation for the developmental phenotypes observed in some pregnancies. The AXL protein has been nominated as a key attachment factor for ZIKV in several cell types including NPCs. However, here we show that genetic ablation of AXL has no effect on ZIKV entry or ZIKV-mediated cell death in human induced pluripotent stem cell (iPSC)-derived NPCs or cerebral organoids. These findings call into question the utility of AXL inhibitors for preventing birth defects after infection and suggest that further studies of viral attachment factors in NPCs are needed.

Keywords: AXL; CRISPR/CAS9; TAM receptors; TYRO3; Zika virus; cerebral organoids; induced pluripotent stem cells; microcephaly; neural progenitor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death
  • Cerebrum / pathology*
  • Gene Deletion*
  • Gene Knockout Techniques
  • Humans
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Neural Stem Cells / virology*
  • Neuroprotection*
  • Organoids / metabolism
  • Organoids / pathology
  • Organoids / virology*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Zika Virus Infection / pathology
  • Zika Virus Infection / prevention & control*

Substances

  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase